Considerable public attention has focused recently on the question of why there has been a rather dramatic upsurge in the rate at which the diagnosis of bipolar disorder (BD) is being assigned to children. In large part the upsurge appears to be due to the fact that children with extremely severe irritability, but without distinct manic episodes, are receiving the diagnosis of BD. At the inception of this project, we defined criteria that would allow us to identify reliably children in this controversial diagnostic group. We called the syndrome severe mood and behavioral dysregulation (SMD), and defined it in terms of impairing symptoms that include abnormal baseline mood (i.e. irritability, anger, and/or sadness), hyperarousal (e.g. insomnia, agitation, distractibility), and increased reactivity to negative emotional stimuli. The specific goals of this project are 1) to identify reliably a group of children with severe mood and behavioral dysregulation in order to characterize them clinically and behaviorally, and follow them longitudinally, 2) to compare the brain function of SMD children (assessed with functional MRI and standardized behavioral testing) to that of children with unequivocal BPD;3) to test appropriate treatments for SMD.;and 4) to identify the pathophysiology of severe irritability in youth, in order to foster the development of novel interventions. The latter two goals are particularly important, since if youth with SMD are found to have a form of BD that would dictate one course of treatment, whereas if they are found to have (for example) a variant of depression, anxiety, and/or attention deficit hyperactivity disorder, this would dictate a rather different plan for treatment. Since the inception of this project, approximately 200 youth with SMD have been recruited into the project. Approximately 20 new patients were recruited this year. It is very important to note that these youth with SMD suffer very severe psychiatric impairment, and indeed are as ill as are youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. In past years, we demonstrated that youth with SMD are at risk for major depression, rather than necessarily BD, in early adulthood, and that they are less likely than youth with BD to have a parent with BD. This work in prior years was conducted in epidemiological samples, which have the advantage of representativeness but the disadvantage of relatively few patients with either BD or SMD. This year we published a longitudinal study of our own clinical sample, which had been followed for a median of 28 months. As expected, we found that youth with BD continued to have episodes of mania and hypomania, whereas only a very small percentage of youth with SMD (1/84)developed a hypomanic or manic episode. In previous years, we demonstrated that youth with BD or SMD, but not those with attention deficit hyperactivity disorder (ADHD), anxiety disorders, or unipolar depression, have deficits in face emotion labeling. This year we published data indicating that, while BD and SMD have similar behavioral deficits, the neural mechanisms mediating that dysfunction differ between groups. Specifically, the nature of amygdala dysfunction during face emotion processing differs among youth with BD, SMD, and ADHD. Ongoing work, being prepared for publication, supports the conclusion from this initial study that the neural mechanisms mediating face emotion processing deficits in BD and SMD differ between groups. This new study uses a face processing paradigm where the faces are presented too quickly for conscious processing. The data indicate amygdala dysfunction in youth with SMD even when the faces are presented preconsciously, and suggest that bottom-up attentional mechanisms may be deficient in youth with SMD. An additional study, being prepared for publication, explores response flexibility deficits in SMD and BD youth. Response flexibility deficits could contribute to the frustration experienced by youth with SMD. In this study, we used fMRI in conjunction with a response reversal paradigm and found striatal and ventral prefrontal dysfunction in SMD youth. To further explore the mechanisms mediating frustration in youth with SMD, we built on previous work using a frustrating paradigm (i.e., a rigged game)in the MEG and ERP environments by insituting an fMRI study using a similar paradigm. Finally, from a public health perspective, it is essential to determine whether the distinction between SMD and BD, which is evident in terms of clinical course, family history, and neural circuitry, is also associated with between-group differences in treatment response. In previous work, we found that lithium was not effective in the treatment of SMD. Last year, we began a double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor antidepressant) plus stimulant is more effective than placebo plus stimulant in the treatment of SMD. Recruitment for the study has been extremely robust and youth are tolerating the experimental treatment well.